P673: ASCIMINIB MANAGMENT IN CHRONIC MYELOID LEUKEMIA (CML) PATIENTS WITH T315I MUTATION.
Authors: Elena Kuzmina, Elza Lomaia, Elena Morozova, Ekaterina Chelysheva, Oleg Shukhov, Anna Petrova, Tamara Chitanava, Yulia Vlasova, Evgenia Sbityakova, Tayana Makarova, Irina Nemchenko, Anastasiya Bykova, Margarita Gurianova, Alina Kohno, Anna Turkina
Journal: HemaSphere (2023)

Background: Asciminib mechanism of action differs from other tyrosine kinase inhibitors (TKIs) for it is a Specifically Targeting the ABL Myristoyl Pocket (STAMP) ABL kinase inhibitor, that has a potential efficacy against BCR::ABL1 clones with ATP-binding site mutations, including T315I. In clinical trials in patients (pts) with Ph-positive chronic myeloid leukemia (CML) with T315I mutation, failing other TKIs, it has shown an efficacy and a good safety profile. Asciminib is in use in clinical practice in Russia in Managed Access Program (MAP) supported by Novartis Aims: To present the updated results of the asciminib use in CML patients with the T315I mutation under the MAP in 3 centers of Russia. Methods: In total 82 pts received asciminib in MAP with doses 40/200 mg BID. Twenty-nine were in a 200 mg BID dose group, the data of 24 of them are presented, while 5 pts, who undergone bone marrow transplantation, were excluded from the analysis. Twenty-three pts had T315 mutation, one patient had F317L (T315I detected, but later not confirmed). All pts were adult (>18 years) with Ph-positive CML in chronic phase (CP): 3 were in a second CP after an accelerated phase and 1 – after a blast crisis, all of them had no alternative therapeutic options. Response monitoring and toxicity control were performed according to the MAP treatment plan. Complete cytogenetic response (CCyR - corresponded to BCR::ABL1 ≤1% or MR2), major molecular response (MMR) and deep molecular response (MR4) were assessed by cumulative incident function (CIF) with Gray’s test for comparison responses in subgroups. Survival analysis was performed by Kaplan-Meier method. Results: Median (Me) age at asciminib start was 49 years (range 32-71), the female proportion was 63%. Me of CML duration before asciminib was 6,9 years (range 1-34). All pts received ≥2 prior TKIs, 45% had ≥ 4 prior TKIs. With the Me follow-up period of 21 months (range 6-39); 5 (21%) pts discontinued asciminib (4 due to resistance, 1 due to a clinician decision in achieved MR4). Nine pts had additional chromosomal abnormalities (ACAs) and/or additional BCR::ABL1 mutations in an anamnesis; their responses are presented in a table 1. Six (25%) of 24 pts had ACAs before asciminib, 4 of them achieved MMR, and one of them (№1) was resistant and lost CCyR. Six pts had additional BCR::ABL1 mutations in an anamnesis, 5 of them achieved MMR and 1 pt (№9) was resistant to therapy. Two-years overall survival at 24 months was 100%. Survival rate without treatment discontinuation was 74%. CIF of CCyR, MMR and MR4 at 24 month was 57%, 57% and 34%, respectively. Thirteen (54%) pts were ponatinib-pretreated, and CIF of MMR in ponatinib-naive pts compared to ponatinib-pretreated pts was significantly higher: 90% vs. 25% (p=0.001). In total 4 pts lost CCyR or MMR (table 1). Thirteen (54%) pts experienced adverse events (AEs) of any grade and 4 (17%) had AEs of grade 3 (neutropenia, hypercholesterinemia). No one discontinued treatment due to toxicity. Summary/Conclusion: Highly pre-treated CML pts with T315I mutation are able to achieve a response with asciminib 200 mg BID, especially in ponatinib-naive group. In our pts a safety profile was good with no evidence of severe toxicity. Asciminib shows effectiveness in highly resistant pts with T315I mutation with/without other genetic events (combined mutations, ACAs), though some of them still a challenge for clinicians. Overcoming the resistance by adding other therapy should be investigated.Keywords: Mutation status, BCR::ABL, Asciminib, Chronic myeloid leukemia